Efficient synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-ones catalyzed by dodecylbenzenesulfonic acid in aqueous media under ultrasound irradiation

Article abstract of DOI:10.1016/j.ultsonch.2014.08.024

Synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one derivatives catalyzed by dodecylbenzenesulfonic acid was carried out in 80-92% yields at 40-42 °C within 1-2 h in aqueous media via one-pot three-component condensation of isatoic anhydride, aromatic aldehyde and amine under ultrasound irradiation. Convenient work-up procedures, mild reaction conditions, avoiding the use of organic solvents, and friendly to environment are the salient features of this protocol.

Full text of DOI:10.1016/j.ultsonch.2014.08.024

Accepted Manuscript
Efficient synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-ones cat-
alyzed by dodecylbenzenesulfonic acid in aqueous media under ultrasound
irradiation
Bao-Hua Chen, Ji-Tai Li, Guo-Feng Chen
PII:
S1350-4177(14)00294-6
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2014.08.024
ULTSON 2693
Reference:
Ultrasonics Sonochemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 May 2014
17 August 2014
27 August 2014
Please cite this article as: B-H. Chen, J-T. Li, G-F. Chen, Efficient synthesis of 2,3-disubstituted-2,3-
dihydroquinazolin-4(1H)-ones catalyzed by dodecylbenzenesulfonic acid in aqueous media under ultrasound
irradiation, Ultrasonics Sonochemistry (2014), doi: http://dx.doi.org/10.1016/j.ultsonch.2014.08.024
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Efficient synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-ones catalyzed by
dodecylbenzenesulfonic acid in aqueous media under ultrasound irradiation
Bao-Hua Chena, b, Ji-Tai Lia, *, Guo-Feng Chena
a College of Chemistry and Environmental Science, Hebei University, Baoding 071002, PR China
b College of Pharmaceutical Sciences, Key Laboratory of Pharmaceutical Quality Control of Hebei Province,
Hebei University, Baoding 071002, PR China
Abstract: Synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one derivatives catalyzed by
dodecylbenzenesulfonic acid was carried out in 80%-92% yields at 40-42 oC within 1-2 h in aqueous media via
one-pot three-component condensation of isatoic anhydride, aromatic aldehyde and amine under ultrasound
irradiation. Convenient work-up procedures, mild reaction conditions, avoiding the use of organic solvents, and
friendly to environment are the salient features of this protocol.
Keywords: 2,3-Dihydroquinazolin-4(1H)-one; Catalysis; Condensation; Aqueous media; One-pot synthesis;
Ultrasound irradiation
1. Introduction
2,3-Dihydroquinazolin-4(1H)-one derivatives are an important class of fused heterocyclic compounds and
have been found to posses valuable biological and pharmacological activities [1]. They may display a wide range
of medicinal properties involving antibacterial [2], anticancer [3], antifungal [4], antitumor [5], anticonvulsant
[6], analgesic [7], antihypertension [8], anti-diabetes [9], and some of them have been shown to act as potent
HIV-1 reverse transcriptase inhibitors [10]. In addition, quinazolinone core scaffold can also be found in some
important natural alkaloids [11]. In view of their widely increased application value, investigation on the
synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives has attracted special attention in recent years for the
organic chemists [12].
The synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives was previously carried out by multi-step
reactions [13], which suffered from lengthy procedures or harsh conditions. Comparing with the traditional
methods, multi-component reactions (MCRs) can produce the desired products in a single step and also the
diversity could be achieved simply by varying the reacting components, which has advantages such as milder
reaction conditions, lower cost, shorter reaction time, energy conservation and environment friendly [14]. In
2005, Salehi et al [15] reported a one-pot three-component reaction for the preparation of 2,3-dihydroquinazolin-
*Correspondence author: Ji-Tai Li, College of Chemistry and Environmental Science, Hebei University, Wusi East Road No.180,
Baoding 071002, P.R. China. Tel. +86-312-5079359; Fax: +86-312-5079628; Email address: lijitai@hbu.cn
1

4(1H)-ones via the condensation of isatoic anhydride, aromatic aldehyde and amine catalyzed by silica sulfuric
acid or KAl(SO4)2·12H2O in water and ethanol. Then, similar procedures for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones were presented, using various catalysts such as ethylenediamine diacetate
[16], Ga(OTf)3 [17], citric acid [18], silica-bonded N-propylsulfamic acid [19], silica-bonded S-sulfonic acid [20],
silica sulfuric acid [21], SrCl2·6H2O [22], MCM-41-SO3H [23], magnetic Fe3O4 nanoparticles [24], Al(H2PO4)3
[25], montmorillonite K-10 [26], Al/Al2O3 nanoparticles [27], molecular iodine [28], p-toluenesulfonic acid[29],
and ionic liquid [30], or with the aid of microwave in the presence of Amberlyst-15 [31] or Cu-CNTs [32].
However, some of these methods associated with certain drawbacks such as expensive and large amount of
catalyst, using organic solvent, longer reaction time and lower yields. So, the development of a green, convenient,
efficient method for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones is still in demand.
With the development of green chemistry, the use of non-toxic and environmentally friendly organic solvent
is of much interest. As the most abundant, cheapest, and environmentally friendly solvent, water offers many
practical and economic advantages in organic synthesis including low cost, safe handling and environmental
compatibility. Moreover, water can also exhibit unique reactivity and selectivity in some organic reactions,
which is different from those in conventional organic solvents [33]. Many organic reactions in aqueous media
have been described in the literatures in the past few years [34].
Dodecylbenzenesulfonic acid (DBSA) is an anionic surfactant, which can act as a combined Brønsted acid
surfactant-catalyst. It is both an acid catalyst to activate the substrate molecules and a surfactant to form stable
colloidal dispersion with water-insoluble substrates [35]. Organic reactions catalyzed by proton acid can be
carried out successfully in the presence of water using DBSA [36].
Ultrasound irradiation has been considered as a clean and useful protocol in organic synthesis. Compared
with those traditional methods, ultrasound-assisted organic synthesis has the distinguishing features including
short reaction times, high yields and mild conditions [37]. In recent years, the development of organic reactions
catalyzed by DBSA under ultrasound irradiation in aqueous media has become an area of intense research. Our
laboratory has improved some synthesis of organic compounds using DBSA as catalyst in aqueous media under
ultrasound irradiation，and good results were achieved [38].
To the best of our knowledge, there are no literature examples of the synthesis of 2,3-disubstituted-2,3-
dihydroquinazolin-4(1H)-ones catalyzed by DBSA under ultrasound irradiation. Herein we wish to report an
efficient procedure to synthesize 2,3-dihydroquinazolin-4(1H)-ones through a one-pot three-component
condensation of isatoic anhydride, aromatic aldehyde and amine using DBSA as catalyst in aqueous media under
2

ultrasound irradiation (Scheme 1).
Scheme 1. Synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one derivatives
2. Experimental
2.1. Apparatus, materials and analysis
All chemicals were obtained from commercial suppliers. The liquid aldehydes were distilled before using
and others were used without further purification. Melting points were taken on a TECH X-4 apparatus and were
uncorrected. The NMR spectra was measured on a Bruker AVANCE 600 (600 MHz for 1H and 150 MHz for 13C)
spectrometer using TMS as the internal standard with CDCl3 or DMSO-d6 as solvent. Mass spectrometric data
were determined using a Bruker apex ultra 7.0 T spectrometer. Sonication was performed using a Shanghai
Branson-BUG25-06 or BUG40-06 ultrasonic cleaner (with a frequency of 25 or 40 kHz and a nominal power
250 W), the total acoustic power injected into the sample solution was found to be 0.63 and 1.63 W respectively
by calorimetry [39].
2.2. General procedure for synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-ones
A 25 mL round-bottomed flask was charged with isatoic anhydride (1, 1 mmol), amine (2, 1.2 mmol),
aromatic aldehyde (3, 1 mmol), dodecylbenzenesulfonic acid (0.2 mmol), water (5 mL), and located in the
ultrasonic cleaner, where the surface of reactants was slightly lower than the level of the water in the cleaning
bath. The mixture was irradiated in the water bath of the ultrasonic cleaner at 40-42 oC for the period as indicated
in Table 3. The temperature of the water bath was controlled by addition or removal of circulated water from
ultrasonic bath. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2 : 1, V/V).
After completion of the reaction, the precipitation was filtered and subsequently washed with water (10 mL) and
ethanol to get the crude solid products. The pure products were obtained by recrystallization from ethanol. For
product 4s, after the reaction completed, the mixture was extracted by ethyl acetate (3×3 mL). The combined
organic layer was dried over anhydrous sodium sulfate and filtered. Ethyl acetate was evaporated under reduced
pressure to give the crude product. Pure product 4s was obtained by recrystallization from the mixture of ethanol
3

and petroleum (1 : 2, V/V).
The products 4a-f, 4h-j and 4q-s were known compounds, their authenticity was established by 1H NMR,
13C NMR and their melting points compared with that reported in literatures. The rest products (4g, 4k-p) were
unknown and established by their 1H NMR, 13C NMR and HRMS.
Compound 4a
1
2-Phenyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600 MHz, DMSO-d6): δH
6.30 (d, J = 2.0 Hz, 1H, CH), 6.72 (t, J = 7.5 Hz, 1H, Ph), 6.77 (d, J = 8.1 Hz, 1H, Ph), 7.19 (t, J = 7.2 Hz, 1H,
Ph), 7.26-7.35 (m, 8H, Ph), 7.39 (d, J = 7.5 Hz, 2H, Ph), 7.67 (s, 1H, NH), 7.74 (d, J = 7.7 Hz, 1H, Ph). 13C
NMR (150 MHz, DMSO-d6): δC 73.1, 115.3, 115.8, 118.0, 126.5, 126.7, 127.1, 128.4, 128.8, 128.9, 129.1, 134.2,
141.2, 141.3, 147.1, 162.7.
Compound 4b
2-(4-Chlorphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
DMSO-d6): δH 6.33 (d, J = 2.7 Hz, 1H, CH), 6.74 (t, J = 7.5 Hz, 1H, Ph), 6.77 (d, J = 8.1 Hz, 1H, Ph), 7.21 (t, J
= 7.4 Hz, 1H, Ph), 7.25-7.31 (m, 3H, Ph), 7.35 (t, J = 7.8 Hz, 2H, Ph), 7.37-7.43 (m, 4H, Ph), 7.67 (d, J = 2.5 Hz,
1H, Ph), 7.71-7.75 (m, 1H，NH). 13C NMR (150 MHz, DMSO-d6): δC 72.4, 115.3, 115.8, 118.2, 126.6, 126.7,
128.5, 128.9, 129.0, 129.2, 133.4, 134.3, 140.2, 141.1, 146.9, 162.6.
Compound 4c
2-(4-Methylphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
DMSO-d6): δH 2.22 (s, 3H, CH3), 6.24 (s, 1H, CH), 6.71 (t, J = 7.4 Hz, 1H, Ph), 6.76 (d, J = 8.1 Hz, 1H, Ph),
7.11 (d, J = 7.7 Hz, 2H, Ph), 7.19 (t, J = 7.1 Hz, 1H, Ph), 7.27 (d, J = 7.6 Hz, 5H, Ph), 7.33 (t, J = 7.6 Hz, 2H,
Ph), 7.62 (s, 1H, NH), 7.73 (d, J = 7.6 Hz, 1H, Ph). 13C NMR (150 MHz, DMSO-d6): δC 21.1, 72.9, 115.3, 115.9,
117.9, 126.4, 126.6, 127.0, 128.4, 129.1, 129.4, 134.2, 138.0, 138.3, 141.4, 147.0, 162.8.
Compound 4d
1
2-(4-Nitrolphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, pale yellow solid. H NMR (600 MHz,
DMSO-d6): δH 6.50 (s, 1H, CH), 6.76 (dd, J = 19.4, 7.0 Hz, 2H, Ph), 7.23 (s, 1H, Ph), 7.31 (d, J = 6.7 Hz, 3H,
Ph), 7.36 (d, J = 6.7 Hz, 2H, Ph), 7.66 (d, J = 6.7 Hz, 2H, Ph), 7.74 (d, J = 6.4 Hz, 1H, Ph), 7.82 (s, 1H, NH),
8.20 (d, J = 7.2 Hz, 2H, Ph). 13C NMR (150 MHz, DMSO-d6): δC 72.2, 115.4, 115.8, 118.5, 124.2, 126.6, 126.7,
128.4, 128.6, 129.3, 134.5, 141.0, 146.6, 147.9, 148.5, 162.4.
Compound 4e
4

2-(4-Methoxyphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
DMSO-d6): δH 3.69 (d, J = 1.6 Hz, 3H, OCH3), 6.23 (s, 1H, CH), 6.72 (t, J = 6.4 Hz, 1H, Ph), 6.76 (d, J = 7.3 Hz,
1H, Ph), 6.86 (d, J = 6.7 Hz, 2H, Ph), 7.19 (d, J = 6.2 Hz, 1H, Ph), 7.23-7.38 (m, 7H, Ph), 7.57 (s, 1H, NH), 7.73
(d, J = 7.4 Hz, 1H, Ph). 13C NMR (150 MHz, DMSO-d6): δC 55.5, 72.8, 114.1, 115.3, 115.8, 117.9, 126.4, 126.8,
128.4, 128.4, 129.0, 133.1, 134.2, 141.3, 147.1, 159.6, 162.8.
Compound 4f
2-(2-Chlorphenyl)-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz, CDCl3):
δH 5.30 (s, 1H, CH), 6.43 (s, 1H, Ph), 6.57 (d, J = 8.0 Hz, 1H, Ph), 6.86 (t, J = 7.5 Hz, 1H, Ph), 7.18-7.26 (m, 5H,
Ph), 7.28 (s, 1H, Ph), 7.32 (t, J = 7.8 Hz, 2H, Ph), 7.37 (d, J = 7.6 Hz, 1H, Ph), 7.58 (d, J = 7.5 Hz, 1H, Ph), 8.03
(d, J = 7.7 Hz, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 71.1, 114.9, 116.6, 119.6, 125.8, 126.7, 127.3, 128.2,
129.0, 130.1, 130.3, 131.5, 134.1, 136.8, 140.8, 144.8, 163.3. HRMS m/z (ESI): calcd for [C20H15ClN2O+H]+:
335.0946, found 335.0943.
Compound 4g
1
2-(3,4-Methylenedioxyphenyl))-3-phenyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600
MHz, DMSO-d6): δH 5.98 (d, J = 3.2 Hz, 2H, CH2), 6.22 (d, J = 2.5 Hz, 1H, CH), 6.73 (t, J = 7.4 Hz, 1H, Ph),
6.78 (d, J = 8.0 Hz, 1H, Ph), 6.82 (s, 2H, Ph), 6.95 (s, 1H, Ph), 7.20 (t, J = 7.3 Hz, 1H, Ph), 7.27-7.31 (m, 3H,
Ph), 7.35 (t, J = 7.8 Hz, 2H, Ph), 7.59 (d, J = 2.4 Hz, 1H, Ph), 7.74 (d, J = 7.8 Hz, 1H, NH). 13C NMR (150 MHz,
DMSO-d6): δC 72.8, 101.7, 107.3, 108.3, 115.3, 115.8, 118.0, 120.8, 126.5, 126.7, 128.4, 129.1, 134.3, 135.1,
141.2, 147.0, 147.7, 147.8, 162.8. HRMS m/z (ESI): calcd for [C21H16N2O3+H]+: 345.1234, found 345.1230.
Compound 4h
1
2-Phenyl-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600 MHz, CDCl3): δH 2.86
(s, 3H, CH3), 4.69 (s, 1H, CH), 5.70 (s, 1H, Ph), 6.54 (d, J = 8.0 Hz, 1H, Ph), 6.82 (t, J = 7.5 Hz, 1H, Ph), 7.24 (t,
J = 7.5 Hz, 1H, Ph), 7.36 (dd, J = 4.7, 1.3 Hz, 3H, Ph), 7.39 (dd, J = 6.5, 2.8 Hz, 2H, Ph), 7.93 (d, J = 7.8 Hz, 1H,
NH). 13C NMR (150 MHz, CDCl3): δC 32.0, 74.2, 114.1, 115.6, 119.1, 126.8, 128.5, 129.1, 129.5, 133.4, 139.5,
145.4, 163.6.
Compound 4i
1
2-(4-Chlorphenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600 MHz, CDCl3):
δH 3.00 (d, J = 4.8 Hz, 3H, CH3), 7.02 (d, J = 7.8 Hz, 1H, CH), 7.37 (t, J = 7.5 Hz, 1H, Ph), 7.48 (t, J = 7.7, 1H,
Ph), 7.52 (d, J = 8.4 Hz, 2H, Ph), 7.82 (d, J = 8.4 Hz, 2H, Ph), 8.32 (d, J = 7.8 Hz, 1H, Ph), 8.40 (s, 1H, Ph), 8.85
5

(s, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 26.5, 118.5, 126.9, 127.0, 129.6, 130.1, 131.3, 132.2, 133.9, 138.6,
148.9, 160.0, 166.6.
Compound 4j
2-(4-Methoxyphenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
CDCl3): δH 2.82 (dd, J = 3.2, 1.3 Hz, 3H, CH3), 3.79 (dd, J = 2.7, 1.0 Hz, 3H, OCH3), 4.59-4.69 (m, 1H, CH),
5.65 (s, 1H, Ph), 6.55 (d, J = 7.9 Hz, 1H, Ph), 6.80-6.83 (m, 1H, Ph), 6.85-6.88 (m, 2H, Ph), 7.23-7.25 (m, 1H,
Ph), 7.31-7.33 (m, 2H, Ph), 7.92 (t, J = 6.5 Hz, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 31.7, 55.4, 73.8,
114.1, 163.8, 114.3, 115.5, 118.9, 128.2, 128.4, 131.5, 133.4, 145.6, 160.4. HRMS m/z (ESI): calcd for
[C16H16N2O2+H]+: 269.1285, found 269.1280.
Compound 4k
2-(4-Methylphenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
CDCl3): δH 2.34 (s, 3H, CH3), 2.85 (s, 3H, CH3), 4.52-4.68 (m, 1H, CH), 5.66 (s, 1H, Ph), 6.53 (d, J = 8.0 Hz,
1H, Ph), 6.81 (t, J = 7.4 Hz, 1H, Ph), 7.16 (d, J = 5.5 Hz, 2H, Ph), 7.22-7.25 (m, 1H, Ph), 7.28 (d, J = 7.8 Hz, 2H,
Ph), 7.93 (d, J = 7.8 Hz, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 21.2, 31.9, 74.0, 114.1, 115.6, 118.9, 126.7,
128.5, 129.7, 133.4, 136.5, 139.4, 145.5, 163.7. HRMS m/z (ESI): calcd for [C16H16N2O+H]+: 253.1335, found
253.1331.
Compound 4l
1
2-(2-Chlorphenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600 MHz, CDCl3):
δH 3.04 (s, 3H, CH3), 5.02 (s, 1H, CH), 6.10 (d, J = 2.1 Hz, 1H, Ph), 6.51 (d, J = 8.1 Hz, 1H, Ph), 6.80 (t, J = 7.5
Hz, 1H, Ph), 7.18-7.27 (m, 4H, Ph), 7.41 (d, J = 7.8 Hz, 1H, Ph), 7.95 (d, J = 7.8 Hz, 1H, NH). 13C NMR (150
MHz, CDCl3): δC 32.9, 70.2, 114.5, 115.6, 119.2, 127.2, 127.5, 128.4, 130.2, 130.3, 132.1, 133.5, 136.0, 144.6,
163.8. HRMS m/z (ESI): calcd for [C15H13ClN2O+H]+: 273.0789, found 273.0784.
Compound 4m
1
2-(4-Nitrophenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, pale yellow solid. H NMR (600 MHz,
CDCl3): δH 3.01 (s, 3H, CH3), 7.07 (d, J = 4.5 Hz, 1H, CH), 7.42 (s, 1H, Ph), 7.52 (s, 1H, Ph), 8.07 (d, J = 5.7
Hz, 2H, Ph), 8.31 (d, J = 4.9 Hz, 1H, NH), 8.40 (d, J = 5.7 Hz, 2H, Ph), 8.55 (s, 2H, Ph). 13C NMR (150 MHz,
CDCl3): δC 26.6, 118.3, 124.4, 127.3, 127.8, 129.6, 131.4, 132.2, 140.5, 148.3, 149.8, 158.9, 166.4. HRMS m/z
(ESI): calcd for [C15H13N3O3+H]+: 284.1030, found 284.1025.
Compound 4n
6

1
2-(2-Nitrophenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, pale yellow solid. H NMR (600 MHz,
CDCl3): δH 3.02 (s, 3H, CH3), 7.12 (s, 1H, CH), 7.41 (s, 1H, Ph), 7.51 (s, 1H, Ph), 7.72 (s, 1H, Ph), 7.82 (s, 1H,
Ph), 8.10 (d, J = 19.0 Hz, 2H, Ph), 8.29 (s, 1H, Ph), 8.57 (s, 1H, Ph), 8.90 (s, 1H, NH). 13C NMR (150 MHz,
CDCl3): δC 26.5, 118.7, 124.9, 127.5, 127.7, 129.6, 130.2, 131.2, 132.1, 132.2, 133.8, 148.3, 149.3, 157.3, 166.5.
HRMS m/z (ESI): calcd for [C15H13N3O3+H]+: 284.1030, found 284.1024.
Compound 4o
2-(2-Methoxyphenyl)-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
CDCl3): δH 3.07 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 5.01 (s, 1H, CH), 6.00 (s, 1H, Ph), 6.47 (s, 1H, Ph), 6.75 (d, J
= 6.2 Hz, 1H, Ph), 6.86 (d, J = 5.9 Hz, 1H, Ph), 6.92 (s, 1H, Ph), 7.07 (s, 1H, Ph), 7.15 (d, J = 5.5 Hz, 1H, Ph),
7.26 (s, 1H, Ph), 7.92 (s, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 33.1, 55.5, 68.6, 110.7, 114.4, 115.7, 118.8,
120.8, 126.3, 126.7, 128.3, 129.8, 133.2, 145.6, 156.5, 164.1. HRMS m/z (ESI): calcd for [C16H16N2O2+H]+:
269.1285, found 269.1280.
Compound 4p
1
2-(3,4-Methylenedioxyphenyl))-3-methyl-2,3-dihydroquinazolin-4(1H)-one, white solid. H NMR (600
MHz, CDCl3): δH 3.01 (d, J = 4.8 Hz, 3H, CH3), 6.09 (s, 2H, CH2), 6.93 (d, J = 8.0 Hz, 1H, CH), 7.00 (d, J = 8.0
Hz, 1H, Ph), 7.30 (dd, J = 8.0, 1.4 Hz, 1H, Ph), 7.33 (t, J = 7.6 Hz, 1H, Ph), 7.42 (d, J = 1.4 Hz, 1H, Ph), 7.46 (td,
J = 7.7, 1.5 Hz, 1H, Ph), 8.29 (s, 1H, Ph), 8.32 (d, J = 7.8, 1.4 Hz, 1H, Ph), 9.02 (s, 1H, NH). 13C NMR (150
MHz, CDCl3): δC 26.5, 102.0, 106.4, 108.6, 118.6, 126.4, 126.6, 126.8, 130.3, 131.2, 132.1, 148.9, 149.3, 151.5,
160.5, 166.7. HRMS m/z (ESI): calcd for [C16H14N2O3+H]+: 283.1077, found 283.1072.
Compound 4q
2-Phenyl-3-(4-methylphenyl)-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
CDCl3): δH 2.25 (s, 3H, CH3), 5.04 (s, 1H, CH), 6.01 (s, 1H, Ph), 6.56 (d, J = 7.9 Hz, 1H, Ph), 6.82-6.84 (m, 1H,
Ph), 7.04 (s, 4H, Ph), 7.23-7.25 (m, 4H, Ph), 7.32-7.33 (m, 2H, Ph), 7.97 (dd, J = 7.9, 1.3 Hz, 1H, NH). 13C
NMR (150 MHz, CDCl3): δC 21.1, 74.7, 114.8, 116.7, 119.3, 126.8, 128.7, 128.9, 128.9, 129.6, 133.8, 136.6,
138.0, 140.1, 145.5, 163.2.
Compound 4r
2-Phenyl-3-(4-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz,
CDCl3): δH 3.72 (s, 3H, CH3), 4.96 (s, 1H, CH), 6.00 (d, J = 1.5 Hz, 1H, Ph), 6.57 (d, J = 8.0 Hz, 1H, Ph),
6.75-6.77 (m, 2H, Ph), 6.84 (t, J = 7.5 Hz, 1H, Ph), 7.03-7.06 (m, 2H, Ph), 7.25 (t, J = 5.0 Hz, 4H, Ph), 7.32 (dd,
7

J = 7.5, 1.9 Hz, 2H, Ph), 7.97 (dd, J = 7.8, 1.3 Hz, 1H, NH), 13C NMR (150 MHz, CDCl3): δC 55.4, 75.0, 114.2,
114.7, 116.6, 119.3, 126.9, 128.5, 128.7, 128.9, 129.0, 133.4, 133.8, 140.0, 145.6, 158.1, 163.3.
Compound 4s
2-Phenyl-3-ethyl-2,3-dihydroquinazolin-4(1H)-one, white solid. 1H NMR (600 MHz, CDCl3): δH 1.12 (t,
J = 7.0 Hz, 3H, CH3), 2.91 (dq, J = 13.6, 6.7 Hz, 1H, CH2), 3.91 (dq, J = 14.0, 7.0 Hz, 1H, CH2), 4.57-4.63 (m,
1H, CH), 5.77 (s, 1H, Ph), 6.52 (d, J = 7.9 Hz, 1H, Ph), 6.83 (d, J = 6.9 Hz, 1H, Ph), 7.23 (t, J = 7.3 Hz, 1H, Ph),
7.35 (s, 3H, Ph), 7.40 (s, 2H, Ph), 7.95 (d, J = 7.3 Hz, 1H, NH). 13C NMR (150 MHz, CDCl3): δC 12.9, 39.5,
72.1, 114.2, 116.2, 119.2, 126.7, 128.4, 129.0, 129.3, 133.4, 139.9, 145.1, 163.0.
3. Results and discussion
To optimize the reaction conditions, synthesis of 2-(4-chlorphenyl)-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one (4b) through the condensation of isatoic anhydride (1 mmol), aniline (1.2 mmol) and
4-chlorobenzaldehyde (1 mmol) in water (5 mL) was selected as the model reaction under ultrasound irradiation.
Table 1. The effect of various catalysts on the yield of 4b under ultrasound irradiationa
Isolated yield, %
Entry
Catalyst
silica sulfuric acid
silica sulfuric acid
p-toluenesulfonic acid
p-toluenesulfonic acid
sulfamic acid
Temperature, oC
23-26
Time, h
1
2
3
4
5
6
7
8
3
2
3
2
3
2
3
2
Trace (TLC)
40-42
25
Trace (TLC)
44
23-26
40-42
23-26
Trace (TLC)
20
sulfamic acid
40-42
DBSA
23-26
Trace (TLC)
82
DBSA
40-42
a Isatoic anhydride (0.163 g, 1 mmol), 4-chlorobenzaldehyde (0.141 g, 1 mmol), aniline (0.111 g, 1.2 mmol),
catalyst (0.3 mmol), H2O (5 mL), irradiation frequency 25 kHz.
The effect of various catalysts on the reaction under ultrasound was observed. As shown in Table 1, the
catalysts had a great influence on the reaction yield. No matter which catalyst was used, only trace of product 4b
was detected after 3 h by thin layer chromatography at 23-26 oC under ultrasound irradiation (Table 1, entries 1,
3, 5 and 7). When the reactions catalyzed by silica sulfuric acid, p-toluenesulfonic acid and sulfamic acid were
8

carried out for 2 h at 40-42 oC, the yields of 4b were 25%, 44% and 20% respectively (Table 1, entries 2, 4 and
o
6). However, when the condensation was catalyzed by DBSA for 2 h at 40-42 C, 4b can be obtained in 82%
yield (Table 1, entry 8). It is apparently that DBSA was an efficient catalyst.
To find the optimum amount of DBSA, the yields of the model reaction in water using various amount of
catalyst were obtained and compared. The results are summarized in Table 2. From these results, it can be
concluded that the optimum amount of the catalyst was 0.2 mmol, and 4b was obtained in 85% yield (Table 2,
entry 3). Too much DBSA can’t actually improve the reaction yield (Table 2, entries 4 and 5). It is because high
acid concentration would lead to protonation of the amine, and prevent it from acting as a nucleophile. In the
absence of DBSA, no obviously reaction was taken place at all (Table 2, entry 1). This indicated that DBSA
played an important catalytic role in the reaction under ultrasonication.
Table 2. The effect of reaction conditions on the yield of 4b catalyzed by DBSA
under ultrasound irradiationa
Temperature, oC
Time, h
Isolated yield, %
Entry
DBSA, mmol
1
2
0
40-42
2
2
2
2
2
3
3
2
2
Trace (TLC)
0.1
0.2
0.3
0.4
0.2
0.2
0.2
0.2
40-42
76
3
40-42
85
4
40-42
82
5
40-42
81
Trace (TLC)
6
20-22
7
30-32
54
84
84
8
50-52
9b
40-42
a Isatoic anhydride (0.163 g, 1 mmol), 4-chlorobenzaldehyde (0.141 g, 1 mmol), aniline (0.111 g, 1.2 mmol),
H2O(5 mL), irradiation frequency 25 kHz.
b Irradiation frequency 40 kHz.
The reaction temperature also had significant influence on the reaction yield under ultrasound irradiation.
As shown in Table 2, when the amount of DBSA was 0.2 mmol and other conditions were identical, only trace
of the product was detected by TLC at 20-22 oC for 3 h (Table 2, entry 6), while 85% yield of 4b was obtained at
40-42 oC for 2 h (Table 2, entry 3). The results indicate that increasing the reaction temperature is favorable to
the reaction. The power of sonochemistry comes from the cavitation produced by ultrasound. Increasing the
9

temperature would be helpful to overcome the viscosity of the reaction solution, and raise the vapor pressure of
the medium, which can lead to easier cavitation and accelerate the reaction to occur [37]. However, when the
reaction was carried out at 50-52 oC for 2 h, the yield of 4b was only 84% (Table 2, entry 8). According to the
principle of the cavitation, although increasing temperature can improve the vapor pressure of the solvent and
strengthen the cavitation, meanwhile a large number of cavitation bubbles are generated at higher temperature.
This will act as a barrier to sound transmission and dampen the effective ultrasonic energy from the source which
enters the liquid medium, and lead to decrease in yield [37]. Therefore, the reaction temperature is an important
influencing factor of this procedure under ultrasound irradiation and the proper temperature is 40-42 oC.
The same reaction was carried out with 40 kHz ultrasound irradiation and 4b was afforded in 84% yield
(Table 2, entry 9). The result was similar to the reaction with 25 kHz ultrasound irradiation (Table 2, entry 3). It
seemed that the frequency of irradiation had not significant effect on the yield.
From the above results, the optimized reaction conditions were chosen for the synthesis of
2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one as follows: isatoic anhydride (1, 1 mmol), amine (2, 1.2
mmol), aromatic aldehyde (3, 1 mmol), DBSA (0.2 mmol), water (5 mL), bath temperature 40-42 oC, irradiation
frequency 25 kHz.
Under this condition, a series of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one derivatives were
synthesized by one-pot three-component reaction of isatoic anhydride, aromatic aldehyde and amine using
DBSA as catalyst in aqueous media under ultrasound irradiation. The results are summarized in Table 3
(Method A).
As shown in Table 3, the condensation of isatoic anhydride, aromatic aldehyde and amine catalyzed by
DBSA was carried out in good yield under ultrasound. The dramatic improvements were the short reaction time
and high yield. Comparing with the condensation catalyzed by silica sulfuric acid in refluxing ethanol reported in
the literature [15a], present reaction catalyzed by DBSA in water under ultrasound irradiation was more effective
and environmental friendly. For example, in the reaction catalyzed by silica sulfuric acid in refluxing ethanol, the
synthesis of 4a and 4h needed 6.5 h and 3 h to afford 80% and 82% yield, respectively. Whereas, in the presence
of DBSA and ultrasound irradiation, the same experiment can be finished at 40-42 oC within 1.5 h and 1 h with
83% and 86% yield (Table 3, entries a and h), respectively. It can easily be seen that the ultrasound technique
represented a better procedure in terms of the higher yield and shorter reaction time compared to those
conventional heating methods.
10

Table 3. Synthesis of target compounds catalyzed by dodecylbenzene sulfonic acid in aqueous media with and
without the use of ultrasound irradiationa
Method Ab
Method Bb
Entry
R1
R2
Product
m.p., oC (Lit.)
Time, Isolated Time, Isolated
h
yield, %
83
h
3
yield, %
68
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Me
H
4-Cl
1.5
212-214(209-211)[18]
219-221(217-219)[18]
215-217(215-216)[24]
198-200(196-199)[29]
222-224(218-220)[18]
190-192(212-214)[22]
222-224
a
b
c
4a
4b
4c
4d
4e
4f
2
2
85
88
84
90
80
89
86
88
89
91
82
85
80
85
92
91
89
83
5
4
71
73
67
68
63
76
70
72
68
73
70
67
62
70
75
73
71
68
4-CH3
4-NO2
4-CH3O
2-Cl
2
5
d
e
1.5
2
4
f
4
3,4-(OCH2O)
H
1.5
1
3
g
h
i
4g
4h
4i
2
159-161(160-163) [15a]
186-188(186-188)[15a]
136-138(145-146) [15a]
150-152
Me
4-Cl
1.5
1.5
1
3
Me
4-CH3O
4-CH3
2-Cl
3
j
4j
Me
2
k
l
4k
4l
Me
1.5
1.5
1.5
1.5
1
3
153-155
Me
4-NO2
2-NO2
2-CH3O
3,4-(OCH2O)
H
154-156
3
m
n
o
p
q
r
4m
4n
4o
4p
4q
4r
4s
Me
136-138
3
Me
2.5
2
154-156
Me
165-167
198-200(197-198)[24]
209-211(213-214) [24]
134-136(135-137) [24]
4-CH3C6H4
4-CH3OC6H4
Et
1
2
H
1
2
H
1
2
s
a Isatoic anhydride (1, 1 mmol), amine (2, 1.2 mmol), aromatic aldehyde (3, 1 mmol), DBSA (0.2 mmol), H2O (5 mL),
irradiation frequency 25 kHz, temperature 40-42 oC.
b Method A: ultrasound irradiation. Method B: stirred and refluxed under silent condition
In order to verify the effect of ultrasound irradiation on this reaction, in the absence of ultrasound
11

irradiation, the same experiments for the preparation of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-one
derivatives 4(a-s) were performed with stirring under refluxing conditions (Table 3, Method B). From the results,
we can see that the reactions under refluxing needed longer reaction time (2-5 h) and the yields of the
corresponding products were also lower (62-76%) than that under ultrasound. For example, the synthesis of 4a
and 4h were carried out under refluxing for 3 h and 2 h with the yield of 68% and 70% respectively, while the
same reaction under ultrasound irradiation needed only 1.5 h and 1 h with 83% and 86% yield, respectively
(Table 3, entries a and h). It is clearly that ultrasound irradiation can accelerate the reaction and improve the
results.
The reason may be the cavitation effect produced by the ultrasonication. When ultrasonic waves are
irradiated into the reaction system, cavitation occurs. The violent collapse of the cavitation bubbles generates
localized “hot spots” with transient high pressure and high temperature, which can provide special physical and
chemical conditions for the reaction. This can induce molecular fragmentation, and highly reactive species are
locally produced. In some case, sonication can probably provide more powerful stirring [37]. All these can cause
the reaction to take place rapidly and efficiently.
Table 3 shows the difference in the yield and reaction time for the reactions with different amine. Aliphatic
amine and aromatic amine with electron-donating substituents were more activated and the corresponding yields
were higher than that of aniline (Table 3, entries h, s, q, r and a), while methylamine was better than ethylamine.
The following sequence of reaction (Scheme 2) appears to afford a satisfactory explanation. As shown in
Scheme 2, the carbonyl group of isatoic anhydride could be firstly protonated by DBSA to give intermediate I,
which was then attacked by amine to form intermediate II. Easy or difficult for the amine to attack the carbonyl
and the stability of intermediate II would directly influence the subsequent reactions. Both the methyl and ethyl
are electron-donating groups, while phenyl is electron-withdrawing group and also its size is larger than methyl
and ethyl. This makes methylamine and ethylamine easier attack the positively charged carbon atom of the
carbonyl group than aniline. Within the same reaction time, the yield of the reaction using methylamine as
substrate was higher than that using ethylamine. It is because the size of ethyl was larger than methyl, which
made ethylamine more difficult attack the carbonyl group. For 4-methylaniline and 4-methoxyaniline(Table 3,
entries q and r), in spite of the size of aryl is larger, however methyl and methoxy are electron-donating groups
and can improve the stability of the intermediate II by their conjugation with a positively charged nitrogen,
which is beneficial to the formation of the intermediate II and the subsequent reactions. For this reason,
compared to 4a, 4q and 4r were obtained in higher yields within shorter reaction times (Table 3, entries q, r and
12

a).
HO
OH
NH2 R1
_
O
R1NH2
H
O
O
O
N
N
H
O
O
N
H
O
H
(II)
(I)
O
HO
NH R1
NH R1
OH
- CO2,
- H
NH2
(IV)
N
O
H
(III)
H
ArCH=OH
NH R1
ArCH=O
O
O
NH R1
NH CH Ar
(VI)
- H2O
NH2 CH Ar
OH
(V)
O
O
N
R1
R1
N
N
-H
N
H
Ar
Ar
H2
(VII)
Product
Scheme 2. A possible mechanism of the formation of 2,3-dihydroquinazolin-4(1H)-one
As we can see from Table 3, among the condensation of isatoic anhydride and aniline with aromatic
aldehydes (Table 3, entries a-g), 4-nitrobenzaldehyde in benzene ring with electron-withdrawing substituent
reacted less rapidly than 4-methylbenzaldehyde in benzene ring with electron-donating substituent, and the yield
of 4d (84%) was lower than 4c (88%) (Table 3，entries c and d). It seemed that electronic effect of the
substituted groups in aromatic aldehydes had some influences on the yield of the product. As shown in Scheme 2,
in the formation of 2,3-dihydroquinazolin-4(1H)-one, the protonated aromatic aldehyde firstly reacted with the
13

intermediate IV to form the intermediate V, followed by dehydration to produce the intermediate VI, which
underwent intramolecular cyclization and deprotonation to afford the target compound. Methyl is an
electron-donating group and can be conjugated with C=N through the benzene ring, which made the electron
cloud transfer to the positively charged nitrogen atom and improved the stability of the intermediate VI. Nitro is
an electron-withdrawing group and also can be conjugated with C=N through the benzene ring, but the electron
cloud would transfer to the opposite direction and made the positive charge more concentrated, which may
reduce the stability of the intermediate VI. In the reactions of 2-chlorobenzaldehyde or 4-chlorobenzaldehyde
with isatoic anhydride and aniline, the yield of 4f was lower than 4b (Table 3, entries f and b). It seemed that the
ortho steric effect of chlorine atom in 2-chlorobenzaldehyde hindered the lone electron pair in the nitrogen atom
of anthranilic acid amide (IV) to attack the carbonyl group.
4. Conclusion
In conclusion, we have found an efficient and practical procedure for the synthesis of 2,3-disubstituted-2,3-
dihydroquinazolin-4(1H)-one derivatives via the one-pot three-component condensation of isatoic anhydride,
aromatic aldehyde and amine using dodecylbenzenesulfonic acid as catalyst in aqueous media at 40-42oC under
ultrasound irradiation. The advantages of this method superior to others are facile work-up procedures, mild
conditions, short reaction times, high yields, avoiding the use of organic solvents, and environmental friendly.
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19

Table 1. The effect of various catalysts on the yield of 4b under ultrasound irradiationa
Isolated yield, %
Entry
Catalyst
silica sulfuric acid
silica sulfuric acid
p-toluenesulfonic acid
p-toluenesulfonic acid
sulfamic acid
Temperature, oC
23-26
Time, h
1
2
3
4
5
6
7
8
3
2
3
2
3
2
3
2
Trace (TLC)
40-42
25
Trace (TLC)
44
23-26
40-42
23-26
Trace (TLC)
20
sulfamic acid
40-42
DBSA
23-26
Trace (TLC)
82
DBSA
40-42
a Isatoic anhydride (0.163 g, 1 mmol), 4-chlorobenzaldehyde (0.141 g, 1 mmol), aniline (0.111 g, 1.2 mmol),
catalyst (0.3 mmol), H2O (5 mL), irradiation frequency 25 kHz.
Table 2. The effect of reaction conditions on the yield of 4b catalyzed by DBSA
under ultrasound irradiationa
Temperature, oC
Time, h
Isolated yield, %
Entry
DBSA, mmol
1
2
0
40-42
2
2
2
2
2
3
3
2
2
Trace (TLC)
0.1
0.2
0.3
0.4
0.2
0.2
0.2
0.2
40-42
76
3
40-42
85
4
40-42
82
5
40-42
81
Trace (TLC)
6
20-22
7
30-32
54
84
84
8
50-52
9b
40-42
a Isatoic anhydride (0.163 g, 1 mmol), 4-chlorobenzaldehyde (0.141 g, 1 mmol), aniline (0.111 g, 1.2 mmol),
H2O(5 mL), irradiation frequency 25 kHz.
b Irradiation frequency 40 kHz.
21

Table 3. Synthesis of target compounds catalyzed by dodecylbenzene sulfonic acid in aqueous media with and
without the use of ultrasound irradiationa
Method Ab
Method Bb
Entry
R1
R2
Product
m.p., oC (Lit.)
Time, Isolated Time, Isolated
h
yield, %
83
h
3
yield, %
68
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Me
H
4-Cl
1.5
212-214(209-211)[18]
219-221(217-219)[18]
215-217(215-216)[24]
198-200(196-199)[29]
222-224(218-220)[18]
190-192(212-214)[22]
222-224
a
b
c
4a
4b
4c
4d
4e
4f
2
2
85
88
84
90
80
89
86
88
89
91
82
85
80
85
92
91
89
83
5
4
71
73
67
68
63
76
70
72
68
73
70
67
62
70
75
73
71
68
4-CH3
4-NO2
4-CH3O
2-Cl
2
5
d
e
1.5
2
4
f
4
3,4-(OCH2O)
H
1.5
1
3
g
h
i
4g
4h
4i
2
159-161(160-163) [15a]
186-188(186-188)[15a]
136-138(145-146) [15a]
150-152
Me
4-Cl
1.5
1.5
1
3
Me
4-CH3O
4-CH3
2-Cl
3
j
4j
Me
2
k
l
4k
4l
Me
1.5
1.5
1.5
1.5
1
3
153-155
Me
4-NO2
2-NO2
2-CH3O
3,4-(OCH2O)
H
154-156
3
m
n
o
p
q
r
4m
4n
4o
4p
4q
4r
4s
Me
136-138
3
Me
2.5
2
154-156
Me
165-167
198-200(197-198)[24]
209-211(213-214) [24]
134-136(135-137) [24]
4-CH3C6H4
4-CH3OC6H4
Et
1
2
H
1
2
H
1
2
s
a Isatoic anhydride (1, 1 mmol), amine (2, 1.2 mmol), aromatic aldehyde (3, 1 mmol), DBSA (0.2 mmol), H2O (5 mL),
irradiation frequency 25 kHz, temperature 40-42 oC.
b Method A: ultrasound irradiation. Method B: stirred and refluxed under silent condition
22

Highlights
•
•
•
Efficient one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives.
Reaction catalyzed by dodecylbenzenesulfonic acid under ultrasound irradiation.
Mild conditions, short reaction times, high yields, and environmental friendly.
23